PROJECT SUMMARY/ABSTRACT Hyponatremia is the most common electrolyte disorder encountered clinically. While acute and/or severe hyponatremia is commonly associated with significant symptoms, milder and more chronic forms of hyponatremia remain clinically inconspicuous as the brain effectively adapts to the low extracellular osmolality. However, recent evidence suggests that even mild hyponatremia is associated with subtle neurocognitive deficits, gait disturbances, falls, fractures, and osteoporosis, as well as increased mortality. Current therapeutic interventions for hyponatremia, including fluid restriction and loop diuretics lack clinical trial data to support their efficacy and are commonly associated with poor adherence. The discovery of vasopressin antagonists (vaptans) provided a new drug class targeting the most common mechanism of hyponatremia, i.e., elevated vasopressin. Despite the demonstrated efficacy of vaptans in clinical trials, their use has been limited by high cost as well as safety concerns related to risk of liver injury and the potential for rapid correction of hyponatremia. Thus, despite the significant morbidity and mortality associated with chronic non-severe hyponatremia, there is a paucity of definitively effective, safe, well-tolerated, and reasonably priced treatments. Small European case series have suggested that oral urea is safe and effective for the treatment of hyponatremia. However, urea has not been available for the treatment of hyponatremia in the United States until very recently. Our group recently published the first and only study describing the effectiveness and safety of a new American formulation of oral urea among hospitalized patients with hyponatremia. However, ours was a retrospective study limited to hospitalized patients. Data from large clinical trials on the efficacy of urea for the prevention of patient-centered outcomes in those with chronic hyponatremia are lacking. The current proposal is a pilot study that seeks to establish the feasibility of recruiting ambulatory patients with chronic hyponatremia into a study of urea, determine the acceptability of urea to patients, and explore the effect of this agent on plasma sodium level, neurocognitive function, and postural stability. We will recruit 30 ambulatory patients with chronic non-severe hyponatremia and randomize them to oral urea or no drug treatment for a period of 42 days. Following this initial phase, all patients will have a 10-day washout period, followed by a 42 day period in which subjects initially randomized to no drug therapy will receive urea and those initially treated with urea will receive no drug therapy. We will collect data regarding the ease of recruitment, patient adherence to urea, and adverse events related to its use. We will monitor patients? plasma sodium, neurocognitive function, and postural stability over the course of the study. The feasibility, acceptability, and proof of concept/efficacy data from this pilot study will confirm our group?s capacity to conduct, and will inform the design of a large clinical trial that will assess the efficacy of urea for the prevention of serious clinical outcomes of chronic non-severe hyponatremia.